STUDY QUESTION:Which surgical technique for endometrioma has the least detrimental effect on ovarian reserves? SUMMARY ANSWER:Drainage with hemostatic sealants and cystectomy with ovarian suturing were associated with relatively smaller anti-Müllerian hormone (AMH) declines 3-6 months postoperatively; however, further research assessing fertility and long-term outcomes is needed to clarify the safety and efficacy of these techniques. WHAT IS KNOWN ALREADY:Ovarian endometriomas are common in women of reproductive age and can affect their ability to have a pregnancy. Surgical removal of the endometrioma is one of the strategies to favor pregnancy, with different possible surgical techniques. However, damage to the ovary can result in lower ovarian reserve. To date, it is uncertain what surgical technique provides the best balance between efficacy and safety. STUDY DESIGN SIZE DURATION:We conducted a systematic review and network meta-analysis (NMA), searching PubMed, Embase, and Cochrane Register of Trials for randomized controlled trials (RCTs) that compared the impact of different surgical techniques for endometrioma on ovarian reserves (measured with the AMH level or antral follicle count (AFC)) from inception to June 2024. All relevant peer-reviewed studies were included. PARTICIPANTS/MATERIALS SETTING METHODS:The primary outcome was ovarian reserve, measured by the change in AMH levels (ng/ml) at 3-6 months after the treatment. Secondary outcome was the change in AFC at 3-6 months after the surgery. We assessed the quality of included studies with the Cochrane risk of bias tool 2 and performed an NMA, comparing the head-to-head effect of different surgical strategies, calculating mean differences (MDs) and 95% CIs. MAIN RESULTS AND THE ROLE OF CHANCE:21 RCTs with 1519 participants, comparing 8 different surgical techniques (cystectomy with ovarian suturing, cystectomy with hemostatic sealants, cystectomy with tranexamic acid, cystectomy alone, drainage with hemostatic sealants, drainage alone, laser ablation, and transvaginal sclerotherapy) were included in the systematic review and 17 studies in the NMA. Regarding AMH at 3-6 months after surgery, drainage with hemostatic sealants (MD: 0.96; 95% CI: 0.60-1.33; high level of certainty), cystectomy with ovarian suturing (MD: 0.69; 95% CI: 0.39-0.98; moderate certainty), and cystectomy with hemostatic sealants (MD: 0.37; 95% CI: 0.12-0.61; low certainty) resulted in higher values of AMH compared with cystectomy alone. Regarding AFC at 3-6 months after surgery, laser ablation showed higher values of AFC (MD: 2.30; 95% CI: 0.20-4.40) compared with cystectomy alone at 3-6 months after surgery, followed by cystectomy with ovarian suturing (MD: 1.88; 95% CI: 0.98-2.79). The overall risk of bias of the included studies was low. The Confidence in Network Meta-Analysis (CINeMA) assessment showed that the only comparison with high certainty of evidence is the comparison between cystectomy and drainage with hemostatic sealants, followed by moderate certainty for the comparison between cystectomy and cystectomy with ovarian suturing and between cystectomy and laser, while the remaining comparisons had a low certainty of evidence. LIMITATIONS REASONS FOR CAUTION:The heterogeneity among the included studies, due to differences in the timing of AMH measurement, the localization and size of endometriomas, and the varying surgical techniques and expertise, is the main limitation of this study. In addition, further reasons for caution are the short follow-up period, the lack of data regarding pregnancy rates, and specific interventions such as sclerotherapy. WIDER IMPLICATIONS OF THE FINDINGS:Considering the estimated effect sizes and certainty of evidence for both AMH and AFC, cystectomy with ovarian suturing and drainage with hemostatic sealants were associated with the least negative impact on ovarian reserve markers. Drainage with hemostatic sealants showed associations with higher short-term AMH preservation; however, this is based on limited data, primarily from a single RCT, and more evidence from different centers is needed to assess effectiveness, recurrence risk, and potential adverse effects such as inflammation or fibrosis from allogenic materials. Given the large number of patients operated on for endometriomas globally, we urgently call for well-powered, multicentric RCTs to compare reproductive outcomes across surgical techniques, including those associated with relatively higher AMH in our analysis. STUDY FUNDING/COMPETING INTERESTS:This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors report no relevant conflict of interest. TRIAL REGISTRATION NUMBER:CRD42021238909.

Progestins are important first line and adjuvant medications for endometriosis, yet their efficacy varies among patients. Dienogest (DNG), a 4th generation progestin, is one of the most prescribed and successful progestins, although a subset of patients remain refractory to treatment. A prospective method to match patients to DNG, or other treatments could significantly improve patient outcomes. We employed a multidisciplinary approach using archival patient samples, clinical data, single nuclei sequencing, in silico prediction and high-content organoid drug screening to investigate DNG's impact on endometriotic lesions, signatures of non-response, and treatment options for refractory patients. We found DNG represses the inflammatory phenotype of deeply infiltrating endometriotic lesions by disrupting the chemokine signalling axis. Refractory patients displayed altered epithelial and stromal cell composition, aberrant progesterone receptor co-repressor signalling and enhanced TGF-B mediated fibrosis. Computational drug predictions identified potential therapies for refractory cases, including glucocorticoid receptor agonists for stroma- and immune-rich lesions, and HSP90 or NF-κB inhibitors for epithelial-dominant lesions, the activity of which were validated in high content screening of patient derived organoids. Notably some progestins already approved for endometriosis management possess off-target glucocorticoid activity, providing immediate potential for personalized treatment selection.

Background/Objectives: Postsurgical lower urinary tract dysfunction (LUTD) is a common problem following deep infiltrating endometriosis (DIE) resection. The condition may be caused either by surgically induced damage to the bladder innervation or by pre-existing endometriosis-associated nerve damage. The aim of this study is to evaluate the efficacy of preoperative and postoperative multichannel urodynamic testing (UD) in identifying pre-existing or surgically induced LUTD among patients with DIE. Methods: Women with suspected DIE and planned surgical resection of DIE at the Department of Obstetrics and Gynecology at the University Hospital of Bern from September 2015 to October 2022 were invited to participate in this prospective cohort study. UD was performed before and 6 weeks after surgery. The primary outcome was the maximum flow rate (uroflow), an indicator of LUTD. Secondary outcomes were further urodynamic observations of cystometry and pressure flow studies, lower urinary tract symptoms (LUTS) as assessed by the International Prostate Symptom Score (IPSS), and pain as assessed by the visual analog scale (VAS). Results: A total of 51 patients requiring surgery for DIE were enrolled in this study. All patients underwent surgical excision of the DIE. The cohort demonstrated a uroflow of 22.1 mL/s prior to surgery, which decreased postoperatively to 21.5 mL/s (p = 0.56, 95%CI -1.5-2.71). The mean bladder contractility index (BCI) exhibited a notable decline from 130.4 preoperatively to 116.6 postoperatively (p = 0.046, 95%CI 0.23-27.27). Significant improvements were observed in the prevalence of dysmenorrhea, abdominal pain, dyspareunia, and dyschezia following surgical intervention (p = <0.001). The IPSS score was within the lower moderate range both pre- and postoperatively (mean 8.37 vs. 8.51, p = 0.893, 95%CI -2.35-2.05). Subgroup analysis identified previous endometriosis surgery as a significant preoperative risk factor for elevated post-void residual (43.6 mL, p = 0.026, 95%CI 13.89-73.37). The postoperative post-void residual increased among participants with DIE on the rectum to 54.39 mL (p = 0.078, 95%CI 24.06-84.71). Participants who underwent hysterectomy exhibited a significantly decreased uroflow (16.4 mL/s, p = 0.014, 95%CI 12-20) and BCI (75.1, p = 0.036, 95%CI 34.9-115.38). Conclusions: Nerve-respecting laparoscopy for DIE may alter bladder function. UD is not advisable before surgery, but the measurement may detect patients with LUTD.

Study Objective: To identify characteristics indicating preoperatively the presence of diaphragmatic endometriosis (DE). Design: Comparison of characteristics of patients with diaphragmatic endometriosis (DE) with characteristics of patients with abdominal endometriosis without diaphragmatic involvement, in a prospective cohort study. Setting: Tertiary referral center; endometriosis center. Patients: A total of 1372 patients with histologically proven endometriosis. Interventions: Surgery performed laparoscopically under general anesthesia. All patients with suspected endometriosis underwent a complete bilateral inspection of the diaphragm. Measurements and Main Results: Demographic and clinical pathologic characteristics were evaluated using basic descriptive statistics (comparison of the groups using the x(2) test and the Mann-Whitney t test). A logistic regression analysis was performed to evaluate the relationship (hazard ratio) between symptoms and the presence of DE. DE was diagnosed in 4.7% of the patients (65 of 1372). There was no significant difference between the 2 groups (patients with abdominal endometriosis with or without DE) with regard to typical endometriosis pain (dysmenorrhea, dyschezia, dysuria, and/or dyspareunia). However, in the DE group, diaphragmatic pain was present significantly more often preoperatively (27.7% vs 1.8%, p <.001). Four DE patients (6.1 %) were asymptomatic (with infertility the indication for surgery). In the DE group, 78.4 % had advanced stages of endometriosis (revised American Fertility Society III degrees or IV degrees); the left lower pelvis was affected in more patients (73.8%). In cases of ovarian endometriosis, patients with DE showed a significantly higher prevalence of left ovaries involvement (left 63% vs right 35.7%, p <.001). Patients with DE had a significantly higher rate of infertility (49.2% vs 28.7%, p <. 05). Conclusion: Patients with shoulder pain, infertility, and/or endometriosis in the left pelvis have a significant higher risk of DE and therefore need specific preoperative counseling and if indicated surgical treatment. Journal of Minimally Invasive Gynecology

INTRODUCTION: Ovarian endometrioma is a common subtype of endometriosis with a prevalence between 17 and 44%. The reported average recurrence of endometrioma after surgical management is 21.5% after 2 years and 40-50% after 5 years. The aim of this narrative review was to summarize the existing literature focusing on treatment options after endometrioma recurrence in order to provide an evidence-based approach for the clinical practice.EVIDENCE ACQUISITION: Three electronic databases (MEDLINE, EMBASE and Cochrane) were searched until September 2022 for eligible studies. EVIDENCE SYNTHESIS: The available studies showed that repeated surgery has a negative impact on ovarian function, without improving the fertility outcomes. Transvaginal aspiration as an alternative option for surgery has a high rate of recurrence, which varies from 8.20 to 43.5% depending on the technique used and on the study population. Pregnancy related outcomes were similar between transvaginal aspiration groups and no intervention groups in patients with endo-metrioma recurrence. Regarding medical treatments, only four studies were found, showing that progestins reduce the pain and the diameter of the ovarian cyst.CONCLUSIONS: Recurrent endometrioma is a challenging condition which could be encountered during the care of women with endometriosis. The decision about the treatment-strategy has to be individualized considering family planning status, age, ovarian reserve and transvaginal ultrasound findings. Well-designed randomized clinical trials are needed to export safer conclusions about the most appropriate treatment in each specific condition after endometrioma recurrence.

Leptin has been proposed as a biomarker for endometriosis. Previous studies have shown mixed results. The aim of this study was to compare peritoneal fluid (PF) leptin concentrations between patients with and without endometriosis in a cohort of sufficient size to detect a significant difference

To evaluate the clinical outcomes and prognosis of patients undergoing laparoscopic surgery for tubo-ovarian abscess (TOA) and identify risk factors for pelvic inflammatory disease (PID) recurrence. We conducted a retrospective cohort analysis including 98 women who underwent laparoscopic surgery for TOA at the Department of Obstetrics and Gynecology at the Bern University Hospital from January 2011 to May 2021. The primary outcome studied was the recurrence of PID after TOA surgery. Clinical, laboratory, imaging, and surgical outcomes were examined as possible risk factors for PID recurrence. Out of the 98 patients included in the study, 21 (21.4%) presented at least one PID recurrence after surgery. In the univariate regression analysis, the presence of endometriosis, ovarian endometrioma, and the isolation of E. coli in the microbiology cultures correlated with PID recurrence. However, only endometriosis was identified as an independent risk factor in the multivariate analysis (OR (95% CI): 9.62 (1.931, 47.924), p < 0.01). With regard to the time of recurrence after surgery, two distinct recurrence clusters were observed. All patients with early recurrence (≤ 45 days after TOA surgery) were cured after 1 or 2 additional interventions, whereas 40% of the patients with late recurrence (> 45 days after TOA surgery) required 3 or more additional interventions until cured. Endometriosis is a significant risk factor for PID recurrence after TOA surgery. Optimized therapeutic strategies such as closer postsurgical follow-up as well as longer antibiotic and hormonal therapy should be assessed in further studies in this specific patient population.

A patients' increasing interest in dietary modifications as a possible complementary or alternative treatment of endometriosis is observed. Unfortunately, the therapeutic potential of dietary interventions is unclear and to date no guidelines to assist physicians on this topic exist. The aim of this study, therefore, was to systematically review the existing studies on the effect of dietary interventions on endometriosis. An electronic-based search was performed in MEDLINE and COCHRANE. We included human and animal studies that evaluated a dietary intervention on endometriosis-associated symptoms or other health outcomes. Studies were identified and coded using standard criteria, and the risk of bias was assessed with established tools relevant to the study design. We identified nine human and 12 animal studies. Out of the nine human studies, two were randomized controlled trials, two controlled studies, four uncontrolled before-after studies, and one qualitative study. All of them assessed a different dietary intervention, which could be classified in one of the following principle models: supplementation with selected dietary components, exclusion of selected dietary components, and complete diet modification. Most of the studies reported a positive effect on endometriosis; they were however characterized by moderate or high-risk bias possibly due to the challenges of conducting dietary intervention trials. According to the available level of evidence, we suggest an evidence-based clinical approach for physicians to use during consultations with their patients. Further well-designed randomized controlled trials are needed to accurately determine the short-term and long-term effectiveness and safety of different dietary interventions.

Higher cesarean section rates and better ultrasound diagnostics have led to a more frequent diagnosis of isthmocele, a cesarean scar defect. Sometimes, endometriosis is found in the isthmocele, but simultaneous extrauterine endometriosis and endometriosis in the isthmocele have not yet been reported. Additionally, the surgical technique to repair the isthmocele is the subject of ongoing controversy. The aim of this study is to analyze a possible correlation between uterine scar (isthmocele) endometriosis and extrauterine endometriosis and to investigate the outcome of laparoscopic isthmocele resection in the rendezvous technique. In this single-center retrospective study, we included 83 women of reproductive age with symptomatic isthmocele undergoing laparoscopic isthmocele repair in rendezvous technique from 2004 to 2020 at the University of Bern. We collected data on patient and surgical characteristics as well as on postoperative outcomes (symptoms, further pregnancy, and pregnancy outcomes) retrospectively. We analyzed and compared these data for patients with and without endometriosis. Endometriosis was diagnosed during surgery in 22 out of 83 operated patients (26.5%). Diagnosis of isthmocele endometriosis (n = 9, 11%) was significantly higher in patients with extrauterine endometriosis (n = 6, p = 0.004). While the duration of surgery was significantly longer for patients with endometriosis (p = 0.006), the groups did not differ with regard to blood loss or complications. In addition, both groups showed similar indications for isthmocele repair (infertility, abnormal uterine bleeding, or dysmenorrhea). Surgery significantly improved abnormal uterine bleeding (χ2 p < 0.001), dysmenorrhea (χ2, p = 0.03), and infertility (χ2, p < 0.001). Regardless of the presence of endometriosis, 25 of 40 (63%) infertile patients became pregnant after surgery. In one out of eight pregnancies, however, we observed scar complications during pregnancy such as uterine scar pregnancy (n = 3), uterine scar dehiscence (n = 3), and placenta previa (n = 1). Endometriosis is a non-negligible intraoperative finding in patients with symptomatic isthmocele. The laparoscopic approach in the rendezvous technique is safe and effective. Therefore, this method should be recommended, especially in women with secondary infertility, and preoperatively simultaneous endometriosis resection should be discussed with the patient. In follow-up, postoperative pregnancies have to be monitored with care.

Background There is a growing body of human, animal and in vitro studies on vitamin D (vit D) substitution in endometriosis. The aim of this systematic review is to critically appraise and qualitatively synthesize the results of the available studies that examine the supplementation of vit D for endometriosis treatment. Methods A systematic search of the literature was conducted in four electronic databases (Medline, Cochrane, Scopus, Embase) and grey literature for original research articles on humans, animals and in vitro models published in any language. Results Four human studies, four animal studies and four in vitro studies were included. Quantitative synthesis of human studies showed no significant effect of vit D intake for dysmenorrhea (2 studies, 44 vit D vs 44 placebo, mean -0.71, 95% CI -1.94, 0.51) and non-cyclic pelvic pain (2 studies, 42 vit D vs 38 placebo, mean 0.34, 95% CI -0.02, 0.71). Regarding reproductive outcomes in women with endometriosis after in vitro fertilization, the only available study showed no differences between women taking vit D and women taking placebo. Three of the four included animal studies showed regression of endometriotic implants when treated with vit D. The in vitro studies demonstrated that vit D decreases invasion and proliferation of endometriotic lesions without affecting apoptosis. Conclusions Although in vitro and animal studies suggest regression of the endometriotic implants and decrease of invasion and proliferation after vit D supplementation, this was not reflected in the results of the meta-analysis, which showed no benefit of vit D supplementation in patients with endometriosis and dysmenorrhea or non-cyclic pelvic pain as well as on the outcome of IVF treatment. However, given the heterogeneity and the diversity of the available studies, more research is required to shed light on the role of vit D supplementation in women with endometriosis.

Einleitung Aktuelle Klassifikationssysteme für Endometriose beruhen auf den Ergebnissen eines chirurgischen Eingriffs – meist einer Laparoskopie. Entscheidend für eine erfolgreiche operative Therapie ist jedoch eine möglichst exakte präoperative Beurteilung des Erkrankungsausmaßes. Zusätzlich hat die Bedeutung der nicht-invasiven Diagnostik und der hormonellen Therapie durch das Aufkommen neuer medikamentöser Therapiemöglichkeiten weiter zugenommen. Ziel dieser multizentrischen Studie war es, zu untersuchen, wie exakt die derzeitigen nicht-invasiven diagnostischen Maßnahmen die intraoperative Gesamtsituation bei Endometriose anhand der Enzian-Klassifikation vorhersagen können.

Cellular development is tightly regulated as mature cells with aberrant functions may initiate pathogenic processes. The endometrium is a highly regenerative tissue, shedding and regenerating each month. Endometrial stromal fibroblasts are regenerated each cycle from mesenchymal stem cells and play a pivotal role in endometriosis, a disease characterised by endometrial cells that grow outside the uterus. Why the cells of some women are more capable of developing into endometriosis lesions is not clear. Using isolated, purified and cultured endometrial cells of mesenchymal origin from 19 women with ( n = 10) and without ( n = 9) endometriosis we analysed the transcriptome of 33,758 individual cells and compared these to clinical characteristics and in vitro growth profiles. We show purified mesenchymal cell cultures include a mix of mesenchymal stem cells and two endometrial stromal fibroblast subtypes with distinct transcriptomic signatures indicative of varied progression through the differentiation processes. The fibroblast subgroup characterised by incomplete differentiation was predominantly (81%) derived from women with endometriosis and exhibited an altered in vitro growth profile. These results uncover an inherent difference in endometrial cells of women with endometriosis and highlight the relevance of cellular differentiation and its potential to contribute to disease susceptibility.

Supplemental Digital Content is Available in the Text. Targeted lipids and inflammation modulators were analyzed in abdominal fluid and serum revealing an association between endocannabinoids (2-AG and AEA) and gynecological pain.

Objective To assess the diagnostic performance of preoperative application of the Enzian classification (cEnzian) using surgical findings as reference standard. Design A prospective international non-interventional study. Setting Twelve endometriosis centres in four European countries (Austria, Germany, Switzerland and Czech Republic). Population 1062 women with endometriosis surgery. Methods Extent of endometriosis was preoperatively classified using the cEnzian classification based on gynaecological examination and/or transvaginal ultrasound (TVS) and/or magnetic resonance imaging (MRI). After subsequent surgery, the surgeon classified the intraoperative findings using the Enzian classification. Main outcome measures Sensitivity, specificity, PPV, NPV, LR+, LR- and accuracy were calculated. Conditional frequencies of intraoperative Enzian codings and the corresponding 95% confidence intervals were computed for each preoperative coding and visualised in plots. Results Although overall consistency of cEnzian and Enzian was poor (35.14%, 95% confidence interval 32.26-38.03), high specificities and negative predictive values (NPVs) of the cEnzian compartments could be demonstrated. Looking at the individual parts of the Enzian classification, the poorest diagnostic performance was detected for compartment B and the highest PPVs were found for category 3 lesions (>3 cm), independent of the compartment. Conclusions Using the Enzian classification in a non-invasive setting is a useful tool providing us with an 'at a glance' summary of the diagnostic workup regarding deep endometriosis with high specificities and NPVs. An attempt to merge the two new endometriosis classification systems (#Enzian and AAGL 2021) seems reasonable taking into consideration the respective advantages of each other.

Aim: Individuals with SARS-CoV-2 infection and (pre-existing) diabetes, including pregnant women, present with more severe morbidity, as compared to non-diabetic subjects. To date, evidence is limited concerning the role of gestational diabetes (GDM) in severity of SARS-CoV-2 infection during pregnancy, or vice versa. The aim of our study was to investigate the prevalence of GDM in a SARS-CoV-2 infected pregnant population and evaluate risk factors for and from severe infection in these patients. Methods: A case-control study with prospective data collection for the case group and 1:2 matching with historical controls based on parity, BMI and ethnicity was conducted (n = 224). GDM screening was performed at 26 weeks' gestation. Multivariate binary logistic regression analysis was performed to assess risk factors for GDM and inpatient COVID-19 management. Results: 34.6% of the patients in the case group suffered from GDM, vs. 16.1% in the control group (p = 0.002). 35.7% patients were diagnosed with GDM after, vs. 33.3% before SARS-CoV-2 infection (OR (95%CI) 1.11(0.40 -3.08), p = 0.84), with no correlation between time point of infection and GDM diagnosis. SARS-CoV-2 (OR (95%CI) 2.79 (1.42, 5.47), p = 0.003) and BMI (OR (95%CI) 1.12 (1.05, 1.19), p = 0.001) were significant independent risk factors for GDM. Conclusion: Data suggests that GDM increases the risk of infection in SARS-CoV-2 infected pregnant women. Meanwhile, SARS-CoV-2 during pregnancy might increase the risk of developing GDM. Vaccination and caution in using protective measures should be recommended to pregnant women, particularly when suffering from GDM. (c) 2022 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Endometriosis is a common gynaecological condition characterised by the growth of endometrial tissue outside the uterus and is associated with pain and infertility. Currently, the gold standard for endometriosis diagnosis is laparoscopic excision and histological identification of endometrial epithelial and stromal cells. There is, however, currently no known association between the histological appearance, size, morphology, or subtype of endometriosis and disease prognosis. In this study, we used histopathological software to identify and quantify the number of endometrial epithelial and stromal cells within excised endometriotic lesions and assess the relationship between the cell contents and lesion subtypes. Prior to surgery for suspected endometriosis, patients provided menstrual and abdominal pain and dyspareunia scores. Endometriotic lesions removed during laparoscopic surgery were collected and prepared for immunohistochemistry from 26 patients. Endometrial epithelial and stromal cells were identified with Cytokeratin and CD10 antibodies, respectively. Whole slide sections were digitised and the QuPath software was trained to automatically detect and count epithelial and stromal cells across the whole section. Using this classifier, we identified a significantly larger number of strongly labelled CD10 stromal cells (p = 0.0477) in deeply infiltrating lesions (99,970 ± 2962) compared to superficial lesions (2456 ± 859). We found the ratio of epithelial to stromal cells was inverted in deeply infiltrating endometriosis lesions compared to superficial peritoneal and endometrioma lesions and we subsequently identified a correlation between total endometrial cells and abdominal pain (p = 0.0005) when counted via the automated software. Incorporating histological software into current standard diagnostic pipelines may improve endometriosis diagnosis and provide prognostic information in regards to severity and symptoms and eventually provide the potential to personalise adjuvant treatment decisions.

Introduction: Endometriosis is an inflammatory condition, affecting mainly women of reproductive age. Leptin is a regulator of food intake and energy expenditure, posing pleiotropic actions, and regulating immunity and fertility. The aim of this study was to systematically review the literature regarding leptin concentrations in biological fluids and tissues of women with endometriosis, and to investigate and propose a possible role of leptin in the pathophysiology of endometriosis. Materials and methods: A systematic search of the literature was conducted in two electronic databases (MEDLINE, COCHRANE) and grey literature for original research articles on humans, published in any language. . Results: Twenty-nine studies with 1291 women with endometriosis and 1664 controls were included in the systematic review. Peritoneal fluid and follicular fluid leptin concentrations were higher in endometriosis compared with control group [mean difference (MD) 7.10, 95 % confidence interval (CI) 4.76 to 9.44 ng/mL, 18 studies), (MD 1.35, 95 % CI 0.54-2.17 ng/ml, 2 studies) respectively. No differences were evident in serum (MD 0.92, 95 % CI -0.84 to 2.68 ng/mL, 12 studies) or plasma (MD -0.95, 95 % CI -4.63 to 2.72 ng/mL, 3 studies) between the groups. No meta-analysis was conducted for ovarian tissue leptin (2 studies). Conclusions: This meta-analysis provided evidence for increased leptin concentrations in both peritoneal fluid and follicular fluid of women with endometriosis compared with control; these differences were not present in the serum or plasma. The above results support a potential pathophysiologic role for leptin in the local microenvironment while declines its use as a blood diagnostic marker. Furthermore, we propose a possible role of leptin in the pathophysiology of endometriosis.